Anti-bacterial, anti-biofilm and synergistic effects of phenazine-based ruthenium(II) complexes.

Antimicrobial resistance has become a global threat to human health, which is coupled with the lack of novel drugs. Metallocompounds have emerged as promising diverse scaffolds for the development of new antibiotics. Herein, we prepared some metal compounds mainly focusing on cis-[Ru(bpy)(dppz)(SO3)(NO)](PF6) (PR02, bpy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), in which phenazinic and nitric oxide ligands along with sulfite conferred some key properties. This compound exhibited a redox potential for bound NO+/0 of -0.252 V (vs. Ag|AgCl) and a high pH for nitrosyl-nitro conversion of 9.16, making the nitrosyl ligand the major species. These compounds were still able to bind to DNA structures. Interestingly, reduced glutathione (GSH) was unable to promote significant NO/HNO release, an uncommon feature of many similar systems. However, this reducing agent was essential to generate superoxide radicals. Antimicrobial studies were carried out using six bacterial strains, where none or very low activity was observed for Gram-negative bacteria. However, PR02 and PR (cis-[Ru(bpy)(dppz)Cl2]) showed high antibacterial activity in some Gram-positive strains (MBC for S. aureus up to 4.9 µmol L-1), where the activity of PR02 was similar to or at least 4-fold better than that of PR. Besides, PR02 showed capacity to inhibit bacterial biofilm formation, a major health issue leading to bacterial tolerance to antibiotics. Interestingly, we also showed that PR02 can function in synergism with the known antibiotic ampicillin, improving their action up to 4-fold even against resistant strains. Altogether, these results showed that PR02 is a promising antimicrobial nitrosyl ruthenium compound combining features beyond its killing action, which deserves further biological studies.

Incorporation of Nitroprusside on Silica Nanoparticles-A Strategy for Safer Use of This NO Donor in Therapy.

Silica-based nanoparticles have been developed as powerful platforms for drug delivery and might also prevent undesired side effects of drugs. Here, a fast method to synthesize positively charged mesoporous silica nanoparticles (ζ = 20 ± 0.5 mV, surface area = 678 m2 g-1, and 2.3 nm of porous size) was reported. This nanomaterial was employed to anchor sodium nitroprusside (SNP), a vasodilator drug with undesired cyanide release. A remarkable incorporation of 323.9 ± 7.55 µmol of SNP per gram of nanoparticle was achieved, and a series of studies of NO release were conducted, showing efficient release of NO along with major cyanide retention (ca. 64% bound to nanoparticle). Biological assays with mammalian cells showed only a slight drop in cell viability (13%) at the highest concentration (1000 µM), while SNP exhibited an LC50 of 228 µM. Moreover, pharmacological studies demonstrated similar efficacy for vasodilation and sGC-PKG-VASP pathway activation when compared to SNP alone. Altogether, this new SNP silica nanoparticle has great potential as an alternative for wider and safer use of SNP in medicine with lower cyanide toxicity.

Thiocarbonyl-bound metallonitrosyl complexes with visible-light induced DNA cleavage and promising vasodilation activity.

Nitric oxide has been involved in many key biological processes such as vasodilation, platelet aggregation, apoptosis, memory function, and this has drawn attention to the development of exogenous NO donors. Metallonitrosyl complexes are an important class of these compounds. Here, two new ruthenium nitrosyl complexes containing a thiocarbonyl ligand, with the formula cis-[Ru(phen)2(L)(NO)](PF6)3 (phen = phenantroline, L = thiourea or thiobenzamide), were synthesized and characterized by electronic spectroscopy, FTIR, NMR, mass spectrometry and voltammetric techniques. Theoretical calculations using Density Functional Theory (DFT) and Time-dependent Density Functional Theory (TD-DFT) were also used and further supported the characterizations of these complexes. An efficient release of nitric oxide by blue light was validated using a NO/HNO probe: 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, known as cPTIO. Interestingly, the complex containing thiourea cleaved DNA even in the dark, while both complexes showed great DNA photocleavage activity in blue light. This process might work mainly through NO and hydroxyl radical production. Additionally, these complexes showed promising vasodilator activity, whose mechanism of action was investigated using N-Nitro-l-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and compared to sodium nitroprusside. Both compounds were indeed NO-mediated heme-dependent activators of soluble guanylate cyclase. Additionally, they did not show any significant cytotoxicity against cancer cell lines U87 and GBM02. Altogether, these results supported both complexes having potential pharmacological applications that deserve further studies.

Neuroinhibitory meroterpenoid compounds from Cordia oncocalyx.

Five new meroterpenoid compounds designed as rel-10ß,11ß-epoxy-2,11-dimethoxy-8α-hydroxy-8aß-methyl-5α,6,7,8,8a,9,10,10aß-octahydro-1,4-anthracendione (1), rel-10ß,11ß-epoxy-8α,5-dihydroxy-2-methoxy-8aß-methyl-5,6,7,8,8a,9,10,10aß-octahydro -1.4-anthracendione (2), rel-1,4,8α-trihydroxy-5-furanyl-2-methoxy-8aß-methyl-6,7,8, 8a,9,10-hexahydro-10-anthracenone (3), rel-10α,11α-epoxy-8α,11ß-dihydroxy-8aß-methyl-5ß,6,7,8,8a,9,10,10aß-octahydro-1,4-anthracenediol (4) and rel-1,4,8α-trihydroxy-5-carboxyethyl-2-methoxy-8aß-methyl-6,7,8,8a,9,10-hexahydro-10-anthra-cenone (5), besides seven (6-12) known compounds were isolated from the heartwood and sapwood ethanol extracts of Cordia oncocalyx. Moreover, the main isolated compounds were screened using the electrically driven mice vas deferens bioassay, which has a rich pharmacological receptors diversity.